Major congenital anomalies, mental retardation or genetic disorders occur in 3-4% of all births, and represent a serious personal, family and societal health burden. While disparate etiologies for these anomalies are recognized, the cause(s) remain unknown in about 65% of cases and in close to 90% of neural tube defects (NTDs). Despite important evidence implicating environmental factors, few definitive associations have been established. This study of 25,700 pregnancies will focus on neural tube and other congenital defects, specifically seeking associations between such defects and periconceptional vitamin A and folic acid consumption, hyperthermia, antecedent spontaneous abortion, spermicides, and other environmental/genetic factors. This data, obtained by broad-based validated questionnaire, will be further correlated with results of neutron activation analysis for specified trace elements in the toenails of all women who bear progeny with a congenital anomaly (about 825, including about 70 NTDs). We plan to use a specially designed questionnaire to prospectively interview 27,500 pregnant women (about 16 wks) undergoing genetic amniocentesis. The amniotic fluid samples of these patients (= 10,000 each year) are all routinely sent for alpha-fetoprotein assay by genetic centers in 22 states to the Center for Human Genetics. Interviews will be concluded prior to completion of the diagnostic assays. Complete data on pregnancy outcome and on infants at 1 year of age (for the presence of congenital defects/developmental disorders) will be obtained. Special methodological considerations include the adequacy of study power, the generalizability of results and the various possible selection, information and confounding biases. This study is unique because (1) it is based upon a large cohort of women at high risk of bearing defective progeny studied in one center, (2) utilizes a validated questionnaire correlated with blood carotene and folate status in an initial cohort of 100 women at 2-8 wks gestation and destined for amniocentesis at 16 wks, (3) is prospective, (4) is in early pregnancy avoiding problems of both recall and subsequent recall bias, (5) of extended follow-up to a year of age, (6) analysis of nails retrospectively reflecting periconceptional trace element status. Elucidation of any causal factors could lead to the reduction in the frequency of neural tube or other congenital defects.